Summary

Background

Among the 30 million patients who undergo non-cardiac surgery yearly,
in the United States, about 3 million have, or are at risk for, coronary
disease. In this subgroup, peri-operative ischemia is a major risk factor
for subsequent events. This study was designed to look at the effect of
peri-operative beta-blockade in preventing ischemia during and immediately
after surgery and, in particular, in reducing cardiac events during the
two years after surgery.

Methods

Subjects: Patients scheduled to undergo elective, non-cardiac surgery
who either had coronary artery disease (history of MI; typical angina;
atypical angina with a positive stress test), or were considered to be
at risk for CAD (two or more of the following: age over 65; hypertension;
current smoking; cholesterol greater than 240; diabetes).

Intervention: Patients were randomized to receive atenolol or placebo.
Atenolol was given IV (5 or 10 mg) or po (50 or 100 mg). The study drug
was given just before surgery, just after surgery and then daily until
hospital discharge or for a maximum of 7 days. The drug was given if the
heart rate was not less than 55 bpm, BP not under 100 mmHg systolic and
there was no evidence of heart block, CHF or bronchospasm. Post-operatively,
the higher doses were given if the HR was over 65 bpm.

Outcomes analysis: Follow-up evaluation was performed 6 months,
one year and two years after surgery. The primary outcome was all-cause
mortality. The secondary outcome was a combination of MI, unstable angina,
revascularization, CHF and death.

Results

Enrolled patients: 200 patients were enrolled (99 atenolol; 101
placebo). There were 6 in-hospital deaths (3 due to MI -- 2 of these in
the placebo group; 3 non-cardiac -- 2 of these in the atenolol group).

There were some differences in baseline characteristics between the
two groups, most of them not statistically significant:

Most of the advantage from atenolol occurred during the first 8 months
(1 death in the atenolol group vs. 10 in the placebo group, 7 from cardiovascular
causes). Thereafter, the survival curves became parallel.

Combined cardiac outcomes: There were 32 cardiac events in the placebo
group vs. 16 in the atenolol group (p=0.08). Again, the advantage of atenolol
occurred during the first 6 to 8 months.

Multivariable analysis: Diabetes was a powerful predictor of two-year
mortality, with a hazard ratio of 2.8 (95% CI 1.4-6.2). The risk related
to diabetes was abolished by atenolol treatment: the hazard ratio for diabetes
in atenolol treated patients was only 1.2, whereas in the placebo group
it was 4.0.

In multivariable analysis, the hazard ratio for atenolol of 0.5 (50%
reduction in risk of death at two years) did not quite reach statistical
significance (p=0.06), presumably because of the powerful predictive value
of diabetes.

Although medications differed between the two groups at baseline and
during follow-up, none of these differences were significantly associated
with two-year mortality.

Tolerance: Over 85% of patients tolerated the administration of
atenolol; over 60% tolerated the full dose. No patients required treatment
for symptomatic hypotension or bradycardia; 3 atenolol patients developed
bronchospasm before surgery.

Authors' Discussion

The effect of peri-operative atenolol on survival (90% in treated patients
at two years vs. 79% for placebo) and event-free survival (83% vs. 68%)
was unexpectedly large, according to the authors. How might a beta-blocker
administered at the time of surgery decrease mortality over the following
half year? The authors do not speculate directly, but they note that peri-operative
ischemia has been associated with a significant increase in cardiac events
over the two years following non-cardiac surgery, and that treatment with
beta-blockers reduces peri-operative ischemia.

Although there were differences in baseline characteristics between
the groups, the authors argue that these do not account for the results.
They state that "a larger proportion of the atenolol-treated patients had
cardiovascular disease before surgery", and that other variables (such
as medications or diabetes) did not account for the results, either.

They conclude that peri-operative beta-blockade in patients with, or
at risk for, coronary artery disease is safe, effective and cost-effective.

Editorial

In an accompanying editorial (the text
is available at the NEJM website), Drs. Kim Eagle and James Froehlich
from the University of Michigan discuss the association between peri-operative
ischemia and post-operative outcome. Surgery causes catecholamine surges
and a prothrombotic state which can, in turn, produce disrupted atherosclerotic
lesions. Such complicated lesions can lead to clinical events in the following
weeks or months. Blocking the peri-operative catecholamine surge could
interrupt this process and might account for the beneficial effect of beta-blockade
that was found in this study.

They note that a number of differences in baseline characteristics which
would bias towards poorer outcome in the placebo group were present in
the study, and that in multivariate analysis only diabetes was a statistically
significant predictor of survival. Nevertheless, the results of this study
do provide evidence for the benefit of peri-operative beta-blockade, particularly
in patients with coronary disease. In addition, they note that a detailed
history, physical examination, EKG and chest x-ray are instrumental in
risk-stratification before non-cardiac surgery and they emphasize the importance
of using the peri-operative period to maximize preventive cardiac care.

Comment

The results of this study are impressive: one week or less of beta-blocker
treatment at the time of non-cardiac surgery led to an absolute reduction
in mortality of 11% over two years.

The baseline characteristics (noted in the table above) do indicate
a number of factors that appear to bias against the placebo group, but
the authors of the article argue convincingly that these do not explain
their results. One objection I have: the baseline numbers appear to show
more prior cardiac disease in the placebo group, but in their discussion
the authors state that there was more prior cardiac disease in the atenolol
group. Since the categories listed under "history of cardiac disease" are
not mutually exclusive, one has to assume that overlap took place in such
a way as to explain this seeming discrepancy. This should have been clarified
in the article.

The authors imply that the improved outcome, which occurred mainly in
the six months following surgery, was due to a reduction in perioperative
ischemia. What evidence is there that such a reduction actually occurred?
No data is given on in-hospital events (apart from the six deaths). In
the methods section of the article, however, the authors state that they
"designed the study to permit the assessment of both in-hospital events
... and adverse cardiovascular outcomes during the two years after discharge".
They supply a reference for in-hospital events in this study, which is
only an abstract (Anesthesiology, 1994;81:Suppl A99).

In that abstract, it is noted that patients were followed with daily
EKG's, Holter monitoring pre-op, intra-op and for 7-days post-op and with
CPK-MB's on days 1 and 5. Ischemic episodes lasting over 1 minute on Holter
were analyzed. Results: the numbers of patients with ischemic episodes
on post-op days 0-2 were 17 in the atenolol group and 34 in the placebo
group (p=0.008). However, atenolol "did not modify the severity of ischemic
episodes" and there was "insufficient power in the study design to demonstrate
a difference in myocardial infarction".

Is this degree of reduction in perioperative ischemia sufficient to
explain the observed reduction in two-year mortality and cardiovascular
events? Perhaps. Alternatively, might beta-blockade inhibit the initiation
of a cascade of events (in part inflammatory?) that begin during surgery
but then evolve on their own over the next few months? The atherosclerotic
process is currently viewed as a very dynamic one. Some theories point
towards an inflammatory (or even infectious) component in its progression.
Such an inflammatory process might be activated by triggers present during
stress, trauma or surgery and a role for the adrenergic system could be
postulated (thanks to Dr. E. Rodney Hornbake of North Shore Hospital for
an informative e-mail exchange on this topic).

Obviously, this is highly speculative. I was not able to find any major
references indicating that beta-blockade would inhibit stress- or trauma-related
inflammation. Nevertheless, an explanation is needed for the impressive
late benefit seen in this study as a result of short-term adrenergic blockade
at the time of surgery. Hopefully, more studies will confirm these results,
analyze them in subgroups (patients with coronary disease and those only
at risk for CAD) and shed some light on the mechanisms involved.

In the meantime, a more liberal use of peri-operative beta-blockers
in patients with, and at risk for, coronary disease certainly seems reasonable.

December 9, 1996

Reader comments

January 23, 1997
From: Kaiser@trip.com.br (Sergio Emanuel Kaiser)

The proportion of patients previously taking beta-blockers was 18% in
the atenolol group and 8% in the placebo group, a meaningful difference
reaching a p level < 0.02.

Could this also suggest a bias toward a selection of patients in the
atenolol group already expected to have a better outcome with perioperative
betablocker use?

Not only was there significantly more beta-blocker use pre-operatively,
in the atenolol group, but also at hospital discharge and at 6 months,
although these numbers were no longer statistically significant. This could
indeed bias the results in favor of atenolol. The authors argue against
this, by noting that beta-blocker use was not significantly associated
with a lower mortality (although the OR was 0.80, the p-value was only
0.73). Nevertheless, this could have contributed to the magnitude of the
effect that was seen in this study. -- mj

June 24, 1997

Letters
to the Editor about this article, from the NEJM website. A number of
criticisms of the study, which the authors rebut convincingly, in my opinion.